Aberrant B cell repertoire selection associated with HIV neutralizing antibody breadth

Area of Science:

• Immunology
• Vaccine Development
• HIV Research

Background:

• HIV vaccine development aims to induce broadly neutralizing antibodies (bNAbs).
• bNAbs often exhibit unique characteristics like long CDR loops, high mutation rates, and polyreactivity.
• It remains unclear if bNAb development stems from inherent antibody repertoire differences or stochastic events.

Purpose of the Study:

• To investigate systematic differences in antibody repertoires associated with the development of broadly neutralizing antibodies (bNAbs) against HIV.
• To identify features of B cell repertoires that correlate with HIV neutralizing antibody breadth.

Main Methods:

• Sequencing of antibody heavy-chain repertoires in a large cohort of HIV-infected individuals with and without bNAb responses, alongside uninfected controls.
• Analysis of B cell repertoire features and correlated T cell phenotypes.
• Comparison with antibody repertoires from individuals with chronic cytomegalovirus infection.

Main Results:

• Identified consistent features within the antibody repertoires of individuals with bNAb responses.
• These features encompassed thousands of B cell clones per individual and were associated with specific T cell phenotypes.
• The observed repertoire features were not present in individuals with chronic cytomegalovirus infection.

Conclusions:

• The development of numerous B cell lineages with antibody features associated with autoreactivity appears to be a key factor in achieving HIV neutralizing antibody breadth.
• This suggests a potential mechanism underlying the generation of effective HIV-specific humoral immunity.